In this competing renewal application, the Principal Investigator wishes to expand his studies on immunotherapy for autoimmune disease by comparing selective anti-TCR therapy with less selective approaches targeting either class II MHC, adhesion molecules or cytokines. Three different models for the induction of relapsing EAE will be utilized; these include 1) spinal cord homogenate, 2) T-cell clones specific for MBP 1-11 and 3) superantigen. Five specific aims are proposed. Aim 1 is to determine whether highly selective anti-TCR therapy will succeed in clinical paradigms where "epitope spreading" might occur. Aim 2 is to determine whether non-selective anti-cytokine therapy or anti- adhesion molecule therapy will be beneficial in clinical paradigms where "epitope spreading" does occur. Aim 3 is to assess the role of the cytokines IL-4 and IL-10 in suppression of EAE. In Aim 4, the role of a variety of adhesion molecules, cytokines, class II and CD4 in selective and non- selective homing to the CNS will be assessed. Aim 5 is to assess the possibility of using DNA vaccination against TCR Vb for treatment of EAE. It is hoped that these studies will provide the basis for future clinical trials in MS patients.